Interpretive Summary: In celiac disease, the systemic tolerance to a common food protein, wheat gluten, is lost and instead, peptides from wheat gluten proteins stimulate an inflammatory response in the small intestine that damages the mucosa and causes malabsorption of nutrients. The basis and mechanism for this loss of tolerance in not understood. In this paper, it is demonstrated that in a stressed environment, retinoic acid, a metabolite of vitamin A, in conjunction with the cytokine IL-15, activates particular cell signaling pathways that lead to the release of proinflammatory cytokines. The role of retinoic acid in the inflammatory response to gluten had not been recognized in prior research.

Technical Abstract:
Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.